Calpains are Ca2+-dependent, heterodimeric cysteine proteases nearly ubiquitous in the cytoplasm of mammalian tissue. These proteins are the only known mammalian proteases known to be activated by calcium, and undergo a very significant structural change upon exposure to this ion. Their activity as proteases is generally restricted to enzyme-processing rather than digestion or degradation. The physiological roles likely involve selective proteolysis of substrates concerned with cytoskeletal remodeling and signal transduction. Some suggested physiological substrates of calpain include protein kinase C and p53 tumor suppressor. Excessive proteolysis by calpains is a feature of pathologies including stroke, cardiac infarct and Alzheimer's disease. There is currently a major effort by the pharmaceutical industry to design inhibitors of calpain. Structural characterization is thus very attractive as it should hasten the design of specific inhibitory drugs as well as provide insight into the biological response to Ca2+.